Randomised clinical trial: linaclotide vs placebo-a study of bi-directional gut and brain axis

Satish S C Rao, Xuelian Xiang, Yun Yan, Kulthep Rattanakovit, Tanisa Patcharatrakul, Rachael Parr, Deepak Ayyala, Amol Sharma, Satish S C Rao, Xuelian Xiang, Yun Yan, Kulthep Rattanakovit, Tanisa Patcharatrakul, Rachael Parr, Deepak Ayyala, Amol Sharma

Abstract

Background: Linaclotide, a guanylate cyclase C agonist relieves irritable bowel syndrome with predominant constipation (IBS-C) symptoms, but how it improves pain in humans is unknown.

Aims: To investigate the effects of linaclotide and placebo on the afferent and efferent gut-brain-gut signalling in IBS-C patients, in a randomised clinical trial.

Methods: Patients with IBS-C (Rome III) and rectal hypersensitivity were randomised (2:1) to receive linaclotide (290 µg) or placebo for 10 weeks and undergo bi-directional gut and brain axis assessment using anorectal electrical stimulations and transcranial/transspinal-anorectal magnetic stimulations. Rectal sensations were examined by balloon distention. Assessments included abdominal pain, bowel symptoms and quality of life (QOL) scores. Primary outcomes were latencies of recto-cortical and cortico-rectal evoked potentials.

Results: Thirty-nine patients participated; 26 received linaclotide and 13 received placebo. Rectal cortical evoked potentials latencies (milliseconds) were significantly prolonged with linaclotide compared to baseline (P1:Δ 19 ± 6, P < 0.005; N1:Δ 20 ± 7, P < 0.02) but not with placebo (P1:Δ 3 ± 5; N1:Δ 4.7 ± 5,P = 0.3) or between groups. The efferent cortico-anorectal and spino-anorectal latencies were unchanged. The maximum tolerable rectal volume (cc) increased significantly with linaclotide compared to baseline (P < 0.001) and placebo (Δ 29 ± 10 vs 4 ± 20, (P < 0.03). Abdominal pain decreased (P < 0.001) with linaclotide but not between groups. Complete spontaneous bowel movement frequency increased (P < 0.001), and IBS-QOL scores improved (P = 0.01) with linaclotide compared to baseline and placebo. There was no difference in overall responders between linaclotide and placebo (54% vs 23%, P = 0.13).

Conclusions: Linaclotide prolongs afferent gut-brain signalling from baseline but both afferent and efferent signalling were unaffected compared to placebo. Linaclotide significantly improves rectal hypersensitivity, IBS-C symptoms and QOL compared to placebo. These mechanisms may explain the effects of linaclotide on pain relief in IBS-C patients. ClinicalTrials.Gov: Registered at Clinical trials.gov no NCT02078323.

© 2020 John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Consort flow diagram for the study
FIGURE 2
FIGURE 2
A, Typical recto‐cortical evoked potential (CEP) responses in IBS‐C patients, before and after treatment with linaclotide and placebo. The latency (onset time) of the P1 and N1 waveforms is significantly prolonged after linaclotide but not after placebo. B, Mean (± SEM) latency time for the onset of P1 and N1 waveforms of the rectal CEP response
FIGURE 3
FIGURE 3
Effects of linaclotide and placebo on A, abdominal pain scores; B, % abdominal pain responders; C, number of complete spontaneous bowel movements (CSBMs)/week; D, % complete spontaneous bowel movement (CSBM) responder; E, % of Composite responders

References

    1. Chang L, Heitkemper M, Wiley J, Camilleri M. 2015 James W. Freston single topic conference: a renaissance in the understanding and management of irritable bowel syndrome. Cellular and Molecular Gastroenterology and Hepatology. 2016. 10.1016/j.jcmgh
    1. Gralnek IM, Hays RD, Kilbourne A, et al. The impact of irritable bowel syndrome on health‐related quality of life. Gastroenterology. 2000;119:654‐660.
    1. Camilleri M, Boeckxstaens G. Dietary and pharmacological treatment of abdominal pain in IBS. Gut. 2017;66:966‐974.
    1. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders. Gastroenterology. 2006;130:1480‐1491.
    1. Drossman DA, Camilleri M, Mayer EA, et al. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002;123:2108‐2131.
    1. Pezzone MA, Liang R, Fraser MO. A model of neural cross‐talk and irritation in the pelvis: implications for the overlap of chronic pelvic pain disorders. Gastroenterology. 2005;128:1953‐1964.
    1. Chan YK, Herkes GK, Badcock C, et al. Alterations in cerebral potentials evoked by rectal distension in irritable bowel syndrome. Am J Gastroenterol. 2001;96:2413‐2417.
    1. Sinhamahapatra P, Saha SP, Chowdhury A, et al. Visceral afferent hypersensitivity in irritable bowel syndrome–evaluation by cerebral evoked potential after rectal stimulation. Am J Gastroenterol. 2001;96:2150‐2157.
    1. Naliboff BD, Derbyshire SWG, Munakata J, et al. Cerebral activation in patients with irritable bowel syndrome and control subjects during rectosigmoid stimulation. Psychosom Med. 2001;63:365‐375.
    1. Kwan CL, Diamant NE, Mikula K, et al. Characteristics of rectal perception are altered in irritable bowel syndrome. Pain. 2005;113:160‐171.
    1. Mayer EA, Tillisch K, Gupta A. Gut/brain axis and the microbiota. J Clin Invest. 2015;125:926‐938.
    1. Coss‐Adame E, Rao SS. Brain and gut interactions in irritable bowel syndrome: new paradigms and new understandings. Curr Gastroenterol Rep. 2014;16:379.
    1. Wilder‐Smith CH, Schindler D, Lovblad K, et al. Brain functional magnetic resonance imaging of rectal pain and activation of endogenous inhibitory mechanisms in irritable bowel syndrome patient subgroups and healthy controls. Gut. 2004;53:1595‐1601.
    1. Brierley SM, Linden DR. Neuroplasticity and dysfunction after gastrointestinal inflammation. Nat Rev Gastroenterol Hepatol. 2014;11:611‐627.
    1. Hobson AR, Aziz Q. Brain imaging and functional gastrointestinal disorders: has it helped our understanding? Gut. 2004;53:1198‐1206.
    1. Coss‐Adame E, Valestin J, Bradley C, et al. Investigation of the efferent spinofugal axis by translumbar and trans‐sacral magnetic stimulation in irritable bowel syndrome (IBS) and interstitial cystitis (IC). Neurogastroenterol Motil. 2012;24:175.
    1. Rao S, Lembo AJ, Shiff SJ, et al. A 12‐week, randomized, controlled trial with a 4‐week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012;107:1714‐1724.
    1. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26‐week, randomized, double‐blind, placebo‐controlled trial to evaluate efficacy and safety. Am J Gastroenterol. 2012;107:1702‐1712.
    1. Rao SSC, Quigley EMM, Shiff SJ, et al. Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation. Clin Gastroenterol Hepatol. 2014;12:616‐623.
    1. Castro J, Harrington AM, Hughes PA, et al. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase‐C and extracellular cyclic guanosine 3',5'‐monophosphate. Gastroenterology. 2013;145(6):1334‐1346. e1–11.
    1. Grundy L, Harrington AM, Castro J, et al. Chronic linaclotide treatment reduces colitis‐induced neuroplasticity and reverses persistent bladder dysfunction. JCI Insight. 2018;3(19). PMID 30282832.
    1. Mohammadi EN, Ligon CO, Silos‐Santiago A, et al. Linaclotide attenuates visceral organ crosstalk: role of guanylate cyclase‐C activation in reversing bladder‐colon cross‐sensitization. J Pharmacol Exp Ther. 2018;366:274‐281.
    1. Castro J, Martin C, Hughes PA, et al. A novel role of cyclic GMP in colonic sensory neurotransmission in healthy and TNBS‐treated mice. Gastroenterology. 2011;140:S‐538.
    1. Rao SSC, Hatfield R, Soffer E, et al. Manometric tests of anorectal function in healthy adults. Am J Gastroenterol. 1999;94:773‐783.
    1. Patrick DL, Drossman DA, Frederick IO, et al. Quality of life in persons with irritable bowel syndrome: development and validation of a new measure. Dig Dis Sci. 1998;43:400‐411.
    1. Remes‐Troche JM, Tantiphlachiva K, Attaluri A, et al. A bi‐directional assessment of the human brain‐anorectal axis. Neurogastroenterol Motil. 2011;23:240‐248, e117–e118.
    1. Remes‐Troche JM, Yamada T, Hamdy S, Rao SSC. Anorectal‐cortical function is impaired in patients with dyssynergic defecation. Gastroenterology. 2007;132:A20.
    1. Coss‐adame E, Remes‐Troche JM, Attaluri A, et al. Does biofeedback therapy improve brain‐gut axis in dyssynergic defecation? Neurogastroenterol and. Motil. 2012;24:S‐367.
    1. Xiang X, Patcharatrakul T, Sharma A, et al. Cortico‐anorectal, Spino‐anorectal, and Cortico‐spinal Nerve Conduction and Locus of Neuronal Injury in Patients With Fecal Incontinence. Clin Gastroenterol Hepatol. 2019;17(1130–1137):e2.
    1. Tantiphlachiva K, Attaluri A, Valestin J, et al. Translumbar and transsacral motor‐evoked potentials: a novel test for spino‐anorectal neuropathy in spinal cord injury. Am J Gastroenterol. 2011;106:907‐914.
    1. Rao SS, Tantiphlachiva K, Remes‐Troche J, et al. Does biofeedback therapy modulate Anorectal (gut)‐brain axis in patients with dyssynergic defecation? Gastroenterology. 2011;140:S‐367.
    1. Loening‐Baucke V, Yamada T. Is the afferent pathway from the rectum impaired in children with chronic constipation and encopresis? Gastroenterology. 1995;109:397‐403.
    1. Ligon C, Mohammadi E, Ge P, et al. Linaclotide inhibits colonic and urinary bladder hypersensitivity in adult female rats following unpredictable neonatal stress. Neurogastroenterol Motil. 2018;30:e13375.
    1. Hannig G, Tchernychev B, Kurtz CB, et al. Guanylate cyclase‐C/cGMP: an emerging pathway in the regulation of visceral pain. Front Mol Neurosci. 2014;7:31.
    1. Wilder‐Smith CH. The balancing act: endogenous modulation of pain in functional gastrointestinal disorders. Gut. 2011;60:1589‐1599.
    1. Faraday M. Experimental research in electricity. Quaritch. 1839;1:1‐15.
    1. Barker AT, Jalinous R, Freeston IL. Non‐invasive magnetic stimulation of human motor cortex. Lancet. 1985;1:1106‐1107.
    1. Turnbull GK, Hamdy S, Aziz Q, et al. The cortical topography of human anorectal musculature. Gastroenterology. 1999;117:32‐39.
    1. Bharucha AE, Linden DR. Linaclotide ‐ a secretagogue and antihyperalgesic agent ‐ what next? Neurogastroenterol Motil. 2010;22:227‐231.
    1. Eutamene H, Bradesi S, Larauche M, et al. Guanylate cyclase C‐mediated antinociceptive effects of linaclotide in rodent models of visceral pain. Neurogastroenterol Motil. 2010;22:312‐e84.
    1. Mayer EA, Berman S, Derbyshire SWG, et al. The effect of the 5‐HT3 receptor antagonist, alosetron, on brain responses to visceral stimulation in irritable bowel syndrome patients. Aliment Pharmacol Ther. 2002;16:1357‐1366.
    1. Silos‐Santiago I, Hannig G, Eutamene H, et al. Gastrointestinal pain: unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase‐C/cGMP activation. Pain. 2013;154:1820‐30.

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